Project Summary Bariatric surgery, in addition to promoting weight loss, has been demonstrated to improve hyperglycemia in diabetic patients. Improvements in glucose control following bariatric procedures like gastric bypass and vertical sleeve gastrectomy (VSG) occur prior to weight loss through mechanisms that are not yet described. A potential mechanism for alleviating diabetes following surgery is that of increased signaling by enteric peptides that act on the islet, known as incretins, given observations that patients receiving VSG display stimulated insulin secretion following oral glucose administration. A mouse model of VSG has been developed that mimics the clinical effects of surgery on glucose homeostasis, ?-cell function, and remarkably, shows stimulation of the ?-cell receptor for glucose-dependent insulinotropic polypeptide (GIP), a prominent incretin. It is unknown how GIP action in the ?-cell is regulated following VSG, or whether GIPR mediates the glucose lowering effects of bariatric surgery. Thus, the goal of this proposal is to test the hypothesis that improved glucose tolerance and ?-cell function after bariatric surgery are mediated by increased GIP action in the ?-cell. This hypothesis will be addressed through two related aims. The first aim is to assess VSG driven changes to GIP sensitivity in the ?-cell by measuring post-VSG insulin secretion in response to exogenous GIP. It is predicted that GIPR signaling will be augmented following VSG. The second aim is to characterize the role of ?-cell GIPR in improving islet function after VSG by measuring glucose tolerance and insulin secretion in mice with ?-cell specific deletion of the GIP receptor following surgery. It is predicted that GIPR deletion will mute the VSG effects on glucose control and ?-cell function. This project employs the robust effects of VSG in mice as a model not only to understand metabolic disease in humans, but also to identify mechanisms necessary for restoring proper islet physiology. Finally, the project will provide a rich training experience that merges cell biology and translational systems, laying a foundation for future, independent research.